ESMO 2018 -Update 4 - GROTHEY.pdf · CheckMate-142 Study Design •CheckMate-142 is an ongoing, multi-cohort, nonrandomized phase 2 study evaluating the efficacy and safety of nivolumab-based

ESMO 2018 - Update

Axel GrotheyWest Cancer Center, U Tennessee

Disclosures• Consulting activities

(honoraria went to the Mayo Foundation or West Cancer Center)• Amgen• Bayer• Pfizer• Roche/Genentech• BMS• Imclone/Eli-Lilly• Boston Biomedicals• ARRAY

I WILL include discussion of investigational or off-label use of a product in my presentation.

Notable Presentations• Colorectal Cancer

• CheckMate 142 - Phase 2 trial of Nivo/ Ipi as first-line therapy in MSI-H/ MMR-D mCRCLenz et al

• MODUL Cohort 2 - Randomized phase 3 trial of maintenance FP/ Atezo/ Bev vs FP/ BEV in first-line mCRC Grothey et al

• TRIBE-2 - Phase 3 trial of first-line FOLFOXIRI/ BEV vs Sequentail FOLFOX/ FOLFIRI + BEV in mCRCCremolini et al

• Non-CRC• TAGS - Phase 3 trial of TAS-102 vs placebo in refractory mCRC

Arkenau et al• Phase Ib trial of Atezo/ BEV as first-line therapy in uHCC

Pishvaian et al

Durable Clinical Benefit With Nivolumab Plus Low-Dose Ipilimumab as First-Line Therapy in Microsatellite Instability-High/Mismatch Repair

Deficient Metastatic Colorectal CancerHeinz-Josef Lenz,1 Eric Van Cutsem,2 Maria Luisa Limon,3 Ka Yeung Mark Wong,4 Alain Hendlisz,5

Massimo Aglietta,6 Pilar García-Alfonso,7 Bart Neyns,8 Gabriele Luppi,9 Dana B. Cardin,10

Tomislav Dragovich,11 Usman Shah,12 Ajlan Atasoy,13 Roelien Postema,13 Zachary Boyd,13 Jean-Marie Ledeine,13 Michael James Overman,14 Sara Lonardi15

1USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA; 2University Hospitals Gasthuisberg/Leuven and KU Leuven, Leuven, Belgium; 3Hospital Universitario Virgen del Rocio, Sevilla, Spain; 4Westmead Hospital, Sydney, Australia; 5Institut Jules Bordet, Brussels, Belgium; 6Candiolo Cancer Institute and University of Torino Medical School, Candiolo, Italy; 7Hospital Gral Universitario Gregorio Marañon, Madrid, Spain; 8University

Hospital Brussels, Brussels, Belgium; 9University Hospital of Modena, Modena, Italy; 10Vanderbilt – Ingram Cancer Center, Nashville, TN, USA; 11Banner MD Anderson Cancer Center, Gilbert, AZ, USA; 12Lehigh Valley Hospital, Allentown, PA, USA; 13Bristol-Myers Squibb, Princeton, NJ, USA;

14The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 15Istituto Oncologico Vento IOV-IRCSS, Padova, Italy

Presentation number: LBA18_PR

HIGHLY CONFIDENTIAL

CheckMate-142 Study Design• CheckMate-142 is an ongoing, multi-cohort, nonrandomized phase 2 study evaluating the

efficacy and safety of nivolumab-based therapies in patients with mCRC (NCT02060188)

• Median follow-up for the 1L nivolumab plus low-dose ipilimumab cohort was 13.8 months (range, 9–19)c

5

CheckMate-142

aUntil disease progression or discontinuation in patients receiving study therapy beyond progression, discontinuation due to toxicity, withdrawal of consent, or the study end; bPatients with a CR, PR, or SD for ≥12 weeks divided by the number of treated patients; cTime from first dose to data cutoffBICR = blinded independent central review; CR = complete response; CRC = colorectal cancer; DCR = disease control rate; DOR = duration of response; PFS = progression-free survival; PR = partial response; Q2W = once every 2 weeks; Q3W = once every 3 weeks; Q6W = once every 6 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease

• Histologically confirmed metastatic or recurrent CRC

• MSI-H/dMMR per local laboratory 1L

Nivolumab 3 mg/kg Q2WaPreviously treated

Previously treatedNivolumab 3 mg/kg +

ipilimumab 1 mg/kg Q3W(4 doses and then

nivolumab 3 mg/kg Q2W)a

Nivolumab 3 mg/kg Q2W +

ipilimumab 1 mg/kg Q6Wa

Primary endpoint: • ORR per investigator

assessment (RECIST v1.1)

Other key endpoints: • ORR per BICR, DCRb,

DOR, PFS, OS, and safety

N=45

Response and Disease Control

Investigator-assessedNivolumab + ipilimumab

N = 45

ORRa, n (%)[95% CI]

27 (60)[44.3–74.3]

Best overall response, n (%)CRPRSDPDNot determined

3 (7)24 (53)11 (24)6 (13)1 (2)

DCRb, n (%)[95% CI]

38 (84)[70.5–93.5]

6

CheckMate-142

aPatients with CR or PR divided by the number of treated patients; bPatients with a CR, PR, or SD for ≥12 weeks divided by the number of treated patientsCI = confidence interval

• Responses were observed regardless of tumor PD-L1 expression, BRAF or KRAS mutation status, or diagnosis of Lynch syndrome

– The ORR and DCR in patients with a BRAF mutation (n = 17) were 71% and 88%, respectively

Investigator-assessedNivolumab + ipilimumab

N = 45

ORRa, n (%)[95% CI]

27 (60)[44.3–74.3]

Best overall response, n (%)CRPRSDPDNot determined

3 (7)24 (53)11 (24)6 (13)1 (2)

DCRb, n (%)[95% CI]

38 (84)[70.5–93.5]

Best Reduction in Target Lesions

7

CheckMate-142

*Confirmed response per investigator assessmentaEvaluable patients per investigator assessment

• 84% of patients had a reduction in tumor burden from baseline

Best

redu

ctio

n fro

m b

asel

ine

in ta

rget

lesi

on (%

)

Patientsa

75

100

50

*****

***

*******************

25

0

–25

–50

–75

–100

–30%

Characterization of Response

8

CheckMate-142

aResponse per investigator assessment

• Median time to response was 2.6 months (range, 1.2–13.8 months)

• Responses were durable:– Median DOR was not reached– 82% of responders had ongoing

responses at data cutoff– 74% of responders have already had

responses lasting ≥6 months – Most responders (96%) were alive at

data cutoff

† †

0 12 24 36 5448 726 18 30 42 60 66 78 84

On treatment

Off treatment

First response

Censored with ongoing responseCensored

Death

Res

pond

ers

(n =

27)

a

Weeks

Progression-Free and Overall Survival

9

CheckMate-142

aPer investigator assessment.mo = month; NE = not estimable; NR = not reached

Nivolumab + ipilimumab

9080706050403020100

0 3 6 9 12 15 18

Pro

gres

sion

-free

sur

viva

l (%

)

Months

No. at risk 45 37 34 24 15 7 7

0 3 6 9 12 15 18 21

Ove

rall

surv

ival

(%)

Months

45 42 40 38 24 13 1 0

100908070605040302010

0

PFSaNivolumab + ipilimumab

N = 45

Median PFS, months (95% CI) NR (14.1–NE)

9-mo rate (95% CI), % 77 (62.0–87.2)

12-mo rate (95% CI), % 77 (62.0–87.2)

OSaNivolumab + ipilimumab

N = 45

Median OS, months (95% CI) NR (NE)

9-mo rate (95% CI), % 89 (74.9–95.1)

12-mo rate (95% CI), % 83 (67.6–91.7)

PFSaNivolumab + ipilimumab

N = 45

Median PFS, months (95% CI) NR (14.1–NE)

9-mo rate (95% CI), % 77 (62.0–87.2)

12-mo rate (95% CI), % 77 (62.0–87.2)

OSaNivolumab + ipilimumab

N = 45

Median OS, months (95% CI) NR (NE)

9-mo rate (95% CI), % 89 (74.9–95.1)

12-mo rate (95% CI), % 83 (67.6–91.7)

Summary and Conclusions• Nivolumab (Q2W) plus low-dose ipilimumab (Q6W) demonstrated robust and durable

clinical benefit as a 1L treatment for MSI-H/dMMR mCRC– High ORR (60%, with 7% CR)– Durable responses (median DOR not reached)– High rate of disease control for ≥12 weeks (84%) – Most patients had a reduction in tumor burden from baseline (84%)– Median PFS and OS not reached with a median follow-up of 14 months– 12-month PFS and OS rates were 77% and 83%, respectively

• Nivolumab plus low-dose ipilimumab was well-tolerated (grade 3–4 TRAEs, 16%) with a low rate of discontinuation due to TRAEs (7%)

• Nivolumab plus low-dose ipilimumab may represent a new 1L treatment option for patients with MSI-H/dMMR mCRC

10

CheckMate-142

esmo.org

Fluoropyrimidine (FP) and bevacizumab � atezolizumab as

first-line treatment for BRAFwt metastatic colorectal cancer:

findings from the MODUL trial of biomarker-driven maintenance

Grothey A,1 Tabernero J,2 Arnold D,3 de Gramont A,4 Ducreux M,5 O’Dwyer PJ,6

Van Cutsem E,7

Bosanac I,8

Srock S,8

Mancao C,8

Gilberg F,8

Winter J,8

Schmoll H-J9

1West Cancer Center, Germantown, TN, USA; 2Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; 3Asklepios Clinic Altona, Hamburg, Germany; 4Franco-British Institute, Levallois-Perret, France; 5Gustave Roussy, Villejuif, Université Paris

Saclay, France; 6Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 7University Hospitals Gasthuisberg, Leuven and KU Leuven, Leuven, Belgium; 8F. Hoffmann-La

Roche Ltd, Basel, Switzerland; 9Martin-Luther-University, Halle, Germany

12

Rationale for combined PD-L1 and VEGF inhibition• In combination, bevacizumab may enhance atezolizumab’s efficacy by reversing VEGF-mediated

immunosuppression to promote T-cell infiltration into the tumour

DC, dendritic cell; MDSC, myeloid-derived suppressor cell; Treg, regulatory T cell

AtezolizumabPromotes T-cell activation

by allowing B7.1 co-stimulation1

BevacizumabPromotes DC maturation2,11,12

BevacizumabNormalizes the tumour vasculature, increasing T-cell infiltration2-6

BevacizumabDecreases the activity of immunosuppressive cells (MDSCs and Tregs)2,3,7-10

AtezolizumabRestores anticancer immunity1 with activity further enhanced through VEGF-mediated immunomodulatory effects

ActivatedT cells

Dendriticcells

Tumourantigens

Tumourcells

1. Chen & Mellman 2013; 2. Hegde et al. 2018; 3. Wallin et al. 2016 4. Goel et al. 2011; 5. Motz et al. 2014; 6. Hodi et al. 2014

7. Gabrilovich & Nagaraj 2009; 8. Roland et al. 2009; 9. Facciabene et al. 2011 10. Voron et al. 2015; 11. Gabrilovich et al. 1996; 12. Oyama et al. 1998

13

MODUL: overall study design

Cohort 1BRAFmut

Cohort 2BRAFwt

R

R

5-FU/LV + cetuximab + vemurafenib

FP + bevacizumab + atezolizumab

FP + bevacizumab

FP + bevacizumab

Induction treatmenta,b Biomarker-driven maintenance treatment

Cohort 3HER2+

FP + bevacizumab

Capecitabine + trastuzumab + pertuzumab

R

Cobimetinib + atezolizumab

FP + bevacizumabCohort 4

HER2– BRAFwtR

TREATMENT

UNTIL

PD

Follow-up

aKey eligibility criteria: histologically confirmed mCRC; measurable, unresectable disease (RECIST 1.1); no prior chemotherapy for mCRC; age ³18 years; ECOG PS £2bPatients with disease progression following Induction treatment can receive further treatment at the discretion of their physician

Primary objective: Progression-free survival (PFS; RECIST v1.1) measured from randomization in each maintenance treatment cohort

Secondary objectives: Overall survival (OS); overall response rate (ORR); disease control rate (DCR); time to treatment response (TTR);

duration of response (DoR); change in ECOG performance status; safety

FOLFOX + bevacizumab8 cycles (16w)

or


then 5-FU/LV +

bevacizumab2 cycles (4w)

CR PR SD

14

MODUL: Cohort 2 (1L BRAFwt)

Cohort 1BRAFmut

Cohort 2BRAFwt

R

R

5-FU/LV + cetuximab + vemurafenib

FP + bevacizumab + atezolizumab

FP + bevacizumab

FP + bevacizumab

Induction treatmenta,b Biomarker-driven maintenance treatment

Cohort 3HER2+

FP + bevacizumab

Capecitabine + trastuzumab + pertuzumab

R

Cobimetinib + atezolizumab

FP + bevacizumabCohort 4

HER2– BRAFwtR

TREATMENT

UNTIL

PD

Follow-up

aKey eligibility criteria: histologically confirmed mCRC; measurable, unresectable disease (RECIST 1.1); no prior chemotherapy for mCRC; age ³18 years; ECOG PS £2bPatients with disease progression following Induction treatment can receive further treatment at the discretion of their physician

Primary objective: Progression-free survival (PFS; RECIST v1.1) measured from randomization in each maintenance treatment cohort

Secondary objectives: Overall survival (OS); overall response rate (ORR); disease control rate (DCR); time to treatment response (TTR);

duration of response (DoR); change in ECOG performance status; safety


or


then 5-FU/LV +

bevacizumab2 cycles (4w)

CR PR SD

15

Patient disposition: Cohorts 1 and 2

FP + bevacizumab + atezolizumab(n=297)

FP + bevacizumab(n=148)

Patients enrolled (n=696)

BRAFwt/BRAF status unknown patients enrolled into Induction

Treatment Populationin Cohort 2 (n=634)

BRAFmut patients enrolled into Induction Treatment Population

in Cohort 1 (n=62; 9%)a

Randomized into Maintenance Treatment in Cohort 2

(n=445)

First randomization: Aug 2015; last patient randomization: 9 Nov 2016Clinical cut-off date: 31 May 2017 (primary analysis); 31 May 2018 (updated analysis)aBRAF mutations were V600; bMain reasons for not being randomized into Maintenance Treatment Population: disease progression, surgery, violation of criteria

Patients screened (n=824)

Not randomized into Maintenance Treatment Population (n=189; 30%)b

2:1 ratio

16Updated analysis: 1L BRAFwt

Median follow-up 18.7 months

OSPFS

FP + bev + atezo FP + bev

Median PFS, months 7.20 7.39

Stratified HR (95% CI) 0.96 (0.77–1.20)p=0.727

FP + bev + atezo FP + bev

Median OS, months 22.05 21.91

Stratified HR (95% CI) 0.86 (0.66–1.13)p=0.283

No. at riskFP+bev+atezo

FP+bev

Time (months)

0 3 6 9 12 15 18 21

1.00

0.75

0.50

0.25

0.00

297 224 147 103 70 49 29 15

148 109 74 55 29 21 17 6

24 27 30

6 1 0

3 1 0

FP + bev + atezoFP + bev

Surv

ival p

robabili

ty

297 293 275 244 214 189 164 104

148 142 130 120 108 94 79 49

70 28 8

30 14 5

0

0

Time (months)

0 3 6 9 12 15 18 21

1.00

0.75

0.50

0.25

0.0024 27 30 33

FP + bev + atezoFP + bev

No. at riskFP+bev+atezo

FP+bev

Surv

ival p

robabili

ty

Median duration of induction treatment phase: 4.1 months; for OS, 51% of patients had an eventOne MSI patient in the FP + bev + atezo arm had a complete response during the maintenance treatment phase

17

All-grade TEAEs in >10% of patients: 1L BRAFwt

No. of patients (%)FP + bev + atezo

(N=293)FP + bev(N=143)

Patients with any TEAEs 276 (94.2) 124 (86.7)

Diarrhoea 66 (22.5) 19 (13.3)

Nausea 57 (19.5) 24 (16.8)

Fatigue 46 (15.7) 22 (15.4)

Palmar-plantar erythrodysaesthesia syndrome 42 (14.3) 25 (17.5)

Hypertension 44 (15.0) 14 (9.8)

Arthralgia 39 (13.3) 4 (2.8)

Pyrexia 32 (10.9) 13 (9.1)

Asthenia 31 (10.6) 11 (7.7)

Peripheral sensory neuropathy 30 (10.2) 15 (10.5)

18

Conclusions: 1L BRAFwt

• MODUL is the largest randomised umbrella maintenance study in the first-line mCRC setting and the largest chemo-immunotherapy study in first-line mCRC reported to date

• Despite activity in other, immune-responsive tumour types, there was no improvement in PFS or OS with the addition of atezolizumab to FP/bevacizumab in the BRAFwt first-line maintenance mCRC population

• The safety profile of atezolizumab + FP/bevacizumab is consistent with previous findings with no new safety signals identified

• Almost all patients in this analysis were MSS. Further efforts are required to find new strategies to circumvent the complex underlying immune escape mechanisms in patients with MSS CRC

TRIBE2: a phase III, randomized strategy study by GONO

in the 1st- and 2nd-line treatment of unresectable

metastatic colorectal cancer (mCRC) patients (pts)

C.Cremolini, C.Antoniotti, S. Lonardi, D. Rossini, F. Pietrantonio, S.S. Cordio, S. Murgioni, F. Marmorino, E. Maiello, A. Passardi, G. Masi, E. Tamburini, D. Santini, R. Grande, A.

Zaniboni, C. Granetto, F. Loupakis, L. Delliponti, L. Boni, A. Falcone

on behalf of the GONO Investigators

2018 ESMO CongressMunich, 19 – 23 October 2018

Study design

R1:1

FOLFOX + bev*

FOLFOXIRI + bev*

PD15FU/bev

5FU/bev

Progression Free Survival 2

FOLFIRI + bev* PD25FU/bev

PD1FOLFOXIRI

+ bev* 5FU/bevPD2

Arm A

Arm B

* Up to 8 cycles

Median follow up = 22.8 mos

Arm AN = 340

Arm BN = 339

Events, N (%) 235 (69%) 188 (55%)

Median PFS2, mos 16.2 18.9

HR = 0.69 [95% CI: 0.57-0.83] p<0.001

Primary endpoint: Progression Free Survival 2

1st line - Safety Profile

G3/4 adverse events, % patients

FOLFOX + bev

N = 336

FOLFOXIRI + bev

N = 336p

Nausea 3 6 0.140

Vomiting 2 3 0.419

Diarrhea 5 17 <0.001

Stomatitis 3 5 0.299

Neutropenia 21 50 <0.001

Febrile neutropenia 3 7 0.050

Neurotoxicity 1 2 0.505

Asthenia 6 7 0.633

Hypertension 10 7 0.223

Venous thromboembolism 6 4 0.204

1st line – RECIST Response Rate

Best Response, %

FOLFOX + bevN = 340

FOLFOXIRI + bevN = 339

OR [95%CI], p

Complete Response 4% 3%

Partial Response 46% 58%

Response Rate 50% 61% 1.55 [1.14-2.10], p=0.005

Stable Disease 40% 31%

Progressive Disease 7% 4%

Not Assessed 3% 4%

1st Progression Free Survival


FOLFOX + bevN = 340

FOLFOXIRI + bevN = 339

Events, N (%) 288 (85%) 261 (77%)

Median PFS, mos 9.9 12.0

HR = 0.73 [95% CI: 0.62-0.87] p<0.001

2nd Progression Free Survival(Patients alive at the time of PD1)


Arm AN = 276

Arm BN = 242

Events, N (%) 223 (81%) 169 (70%)

Median PFS, mos 5.5 6.0

HR = 0.86 [95%CI: 0.70-1.05] p=0.120

Conclusions

ü The upfront exposure to the three cytotoxics provides a significant

advantage when compared with the pre-planned exposure to the same

agents in two subsequent lines of therapy

ü Safety, activity and efficacy results reported with FOLFOXIRI/bev are highly

consistent with those from the previous phase III TRIBE study

ü The choice of the first-line therapy plays a crucial role in the treatment of

mCRC patients as it has a major impact on patients’ outcome

esmo.org

TAGS: A Phase 3, Randomised, Double-blind Study of Trifluridine/Tipiracil (TAS-102) Versus Placebo in Patients With Refractory Metastatic Gastric CancerHendrik-Tobias Arkenau,1 Josep Tabernero,2 Kohei Shitara,3 Mikhail Dvorkin,4 Wasat Mansoor,5 Aliaksandr Prokharau,6Maria Alsina,2 Michele Ghidini,7 Catia Faustino,8 Vera Gorbunova,9 Edvard Zhavrid,10 Kazuhiro Nishikawa,11

Ayumu Hosokawa,12 Doina Ganea,13 Şuayib Yalçın,14 Giordano D Beretta,15 Robert Winkler,16 Lukas Makris,17

Toshihiko Doi,3 David H Ilson18

1Sarah Cannon Research Institute, Cancer Institute, University College London, London, UK; 2Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, Barcelona, Spain; 3National Cancer Center Hospital East, Chiba, Japan; 4Omsk Regional Clinical Centre of Oncology, Omsk, Russian Federation; 5The Christie NHS Foundation Trust, Manchester, UK; 6Minsk City Clinical Oncology Dispensary, Minsk, Belarus; 7Azienda Ospedaliera di Cremona, Cremona, Italy; 8Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal; 9N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation; 10N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus; 11Osaka National Hospital, Osaka, Japan; 12University of Toyama, Toyama, Japan; 13Spitalul Judetean de Urgenta Sfantul Ioan cel NouSuceava, Suceava, Romania; 14Hacettepe University, Ankara, Turkey; 15Humanitas Gavazzeni, Bergamo, Italy; 16Taiho Oncology, Inc., Princeton, NJ, USA; 17Stathmi, Inc, New Hope, PA, USA; 18Memorial Sloan Kettering Cancer Center, New York, NY, USA

TAGS: TAS-102 Gastric Studya

• Treatment until progression, intolerable toxicity, or patient withdrawal

• Multicentre, randomised, double-blind, placebo-controlled, phase 3 study– Stratification: ECOG PS (0 vs 1), region (Japan vs ROW), prior ramucirumab (yes vs no)– Sites: 17 countries, 110 sites; enrolment: February 2016 – January 2018 – Data cutoff date: March 31, 2018– 384 events were targeted to allowed detection of a HR for death of 0.70 with 90% power at 1-sided type 1 error of 0.025

28

BID, twice daily; BSC, best supportive care; ECOG PS, Eastern Cooperative Oncology Group performance status; GEJ, gastroesophageal junction; HER2, human epidermal growth factor receptor 2; ORR, objective response rate; PFS, progression-free survival; QOL, quality of life; R, randomised; ROW, rest of worldaNCT02500043

Endpoints• Primary:

– OS• Key secondary:

– PFS, safety• Other secondary:

– ORR– DCR– QOL– Time to ECOG

PS ≥2

R2:1

Patients with mGC(including GEJ cancer)• ≥2 prior regimens:

– Fluoropyrimidine – Platinum– Taxane and/or irinotecan– HER2 inhibitor, if available, for

HER2+ disease– Refractory to/intolerant

of last prior therapy• ECOG PS of 0 or 1• Age ≥18 y (≥20 y in Japan) Target sample size: 500

FTD/TPI (TAS-102) + BSC(n=337)

35 mg/m2 BID orally on days 1–5 and 8–12 of each 28-day cycle

Placebo + BSC(n=170)

BID orally on days 1–5 and 8–12 of each 28-day cycle

Primary Endpoint – OS

aITT population; bStratified log-rank test 30

FTD/TPI(n=337)a

Placebo(n=170)a

Events, no. (%) 244 (72) 140 (82)

Median, months 5.7 3.6

HR (95% CI) 0.69 (0.56–0.85)

One-sided Pb 0.0003

Two-sided Pb 0.0006

0

20

40

60

80

100

No. at riskFTD/TPIPlacebo

337 124 31 7 1 0240 66 11 4 4 37 49 7102 80 51 40 22 16201 161328 282170 47 10 0 0 0101 29 5 0 0 00 02 240 34 17 12 9 771 60158 131

FTD/TPIPlacebo

OS

(%)

Time (months)0 6 12 18 24 253 9 15 21 22 2319 2016 177 8 10 11 13 144 51 2

12-month OS: 21%

12-month OS: 13%

OS Subgroup Analysis

31

a

Two patients had primary lesions at both sites; this subgroup was not analysed for OS due to insufficient size;

b

HER2 status was not available for 99 patients;

results for these patients are not shown

• Multivariate analysis showed several factors to be prognostic (P<0.05): ECOG PS (0 vs 1), age (<65 vs ≥65 y), prior regimens

(2 vs ≥3), metastatic sites (1 or 2 vs ≥3), and HER2 status (negative vs positive or not done)

• After adjusting for these factors, the treatment effect for FTD/TPI was maintained (HR: 0.69; 95% CI: 0.56–0.85)

228≥65 280≥3

80Asian 286No

Ethnicity 357White Previous gastrectomy 221Yes

3161

338NoECOG PS 1910

Prior ramucirumab 169Yes

Gastric 360

226NoPrimary sitea145GEJ

281YesPrior irinotecan

HER2 statusb94Positive

459YesPrior taxane

408Europe

1943

73Japan

123≥4

138Female 367No

279<65 No. metastatic sites 2271–2Age (years)

Sex 369Male Peritoneal metastases 140Yes

0.5 1.0 1.5 2.0 2.50

313Negative

48No

Favours FTD/TPI Favours placebo

0.5 1.0 1.5 2.0 2.50

PatientsVariable SubgroupPatientsVariable Subgroup HR (95% CI) HR (95% CI)

Favours FTD/TPI Favours placebo

70Other

Region 26USA

1902No. prior regimens

Secondary Endpoint – PFS

32aITT population; bStratified log-rank test

FTD/TPI

Placebo

No. at risk

337 37 4 0122 1832 20 12 9 272 60314 154170 8 1 021 25 2 1 1 112 11145 41

FTD/TPI(n=337)a

Placebo(n=170)a

Events, no. (%) 287 (85) 156 (92)

Median, months 2.0 1.8

HR (95% CI) 0.57 (0.47–0.70)

Two-sided Pb <0.0001

PF

S (

%)

Time (months)

0

20

40

60

80

100

0 6 12 143 97 8 10 11 134 51 2

6-month PFS: 15%

6-month PFS: 6%

FTD/TPIPlacebo

Conclusions

• FTD/TPI showed a clinically meaningful and statistically significant improvement in OS and PFS compared with placebo in heavily pretreated patients with advanced gastric or gastroesophageal junction cancer– 31% reduction in risk of death (HR: 0.69; 95% CI: 0.56–0.85; one-sided P=0.0003;

two-sided P=0.0006)– 2.1-month improvement in median OS (5.7 vs 3.6 months)

• Patients in the FTD/TPI group had a higher DCR (44% vs 14%; two-sided P<0.0001) and lower risk of ECOG PS deterioration to ≥2 (HR: 0.69; 95% CI: 0.56–0.85; two-sided P=0.0005)

• FTD/TPI showed a predictable and manageable safety profile, consistentwith that seen previously in patients with mCRC– Dosing delays were used more frequently than dose reduction to manage AEs– No new safety signals were observed in patients with mGC

• FTD/TPI represents an effective new treatment option with a manageable safety profile for heavily pretreated patients with advanced gastric or gastroesophageal junction cancer

35

esmo.org

Phase Ib study of atezolizumab + bevacizumab in HCC—update on safety and clinical activity

Michael J. Pishvaian,1 Michael S. Lee,2 Baek-Yeol Ryoo,3 Stacey Stein,4 Kyung-Hun Lee,5Wendy Verret,6 Jessica Spahn,6 Hui Shao,6 Bo Liu,6 Koho Iizuka,6 Chih-Hung Hsu7

1 Georgetown University Medical Center, Washington, DC, USA; 2 UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 3 Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; 4 Yale School of Medicine, New Haven, CT, USA; 5 Seoul National University Hospital, Seoul, South Korea; 6 Genentech, Inc., South San Francisco, CA, USA; 7 National Taiwan University Hospital, Taiwan

Pishvaian et al: Atezolizumab + bevacizumab in HCChttp://bit.ly/2y9y1ow

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Phase Ib GO30140 study (NCT02715531)

CTLA-4, cytotoxic T-lymphocyte–associated protein; DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; INV, investigator; IRF, independent review facility; mRECIST, modified Response Evaluation Criteria in Solid Tumours; OS, overall survival; PFS, progression-free survival; PS, performance status; q3w, every 3 weeks; TTRP, time to radiographic progression. a Endpoints per protocol version 5.

At clinical data cutoff (26 July 2018), 103 patients with HCC treated with atezolizumab + bevacizumab were evaluable for safety and 73 patients were evaluable for efficacy with a minimum follow-up of 16 weeks

Until disease progression, unacceptable toxicity or loss

of clinical benefit

Eligibility Criteria:

• Measurable disease per RECIST v1.1

• ECOG PS 0/1

• Adequate haematologic and organ function

• No prior systemic therapy

• No prior treatment with anti–CTLA-4, anti–PD-1 or anti–PD-L1 therapeutic antibodies

Arm A: unresectable or advanced HCC• Up to Child-Pugh score B7

Atezolizumab 1200 mg IV q3w + bevacizumab 15 mg/kg IV q3w

n ≈ 100

Arm B: Gastric cancerArm C: Pancreatic cancerArm E: Oesophageal cancerArm F: Randomised first-line HCC (atezolizumab + bevacizumab vs atezolizumab)

Primary endpointsa (Arm A) § Safety and tolerability, INV-assessed ORR per RECIST v1.1

Key secondary endpoints (Arm A) § INV-assessed DOR, PFS and TTRP per RECIST v1.1

§ IRF-assessed ORR, DOR, PFS and TTRP (all per RECIST v1.1 and HCC mRECIST)

§ OS

IRF = independent review facility


Baseline demographics and clinical characteristics

38

AFP, α-fetoprotein; EHS, extrahepatic spread; HBV, hepatitis B virus; HCV, hepatitis C virus; MVI, macrovascular invasion; TACE, transarterial chemoembolisation.a Missing data are not included.

CharacteristicSafety-evaluable

population(N = 103)

Median age (range), years 62 (23-82)

Sex, n (%)

Male 83 (81)

Female 20 (19)

Region, n (%)a

Asia (excluding Japan) 59 (57)

Japan/USA 42 (41)

ECOG PS, n (%)

0 51 (50)

1 52 (50)

Child-Pugh class, n (%)

A5 76 (74)

A6 21 (20)

B7 6 (6)

CharacteristicSafety-evaluable

population(N = 103)

Cause of HCC, n (%)

HBV 51 (50)

HCV 30 (29)Non-viral 22 (21)

EHS, n (%) 73 (71)

MVI, n (%) 55 (53)EHS and/or MVI, n (%) 90 (87)

AFP, n (%)a

< 400 ng/mL 59 (57)≥ 400 ng/mL 37 (36)

Prior TACE treatment, n (%) 56 (54)

Prior radiotherapy, n (%) 37 (36)


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Safety summary

AE, adverse event; AESI, adverse event of special interest; AST, aspartate aminotransferase, TRAE, treatment-related adverse event.a One Child-Pugh B7 patient developed Grade 4 drug-induced liver injury on Day 8, was treated with prednisone, and recovered. Sepsis occurred on Day 23, leading to hepatic decompensation with encephalopathy, and patient died on Day 38. A second patient developed pneumonitis on Day 20, was treated for pneumonitis and pneumonia and died on Day 22 after refusal of further intensive care. b Any grade or cause. Data cutoff: 26 July 2018.

§ No new safety signals were identified beyond the established safety profile for each individual agent

AEs, n (%) N = 103Any-grade AEs 95 (92)

Treatment related 84 (82)

Grade 3/4 AEs 41 (40)Treatment related 28 (27)

Grade 5 AEs 5 (5)Treatment relateda 2 (2)

Serious AEs 36 (35)Treatment related 19 (18)

Atezolizumab any-grade AESIs 56 (54)Bevacizumab any-grade AESIs 48 (47)

AE leading to withdrawal from

Atezolizumab 8 (8)

Bevacizumab 10 (10)

Both treatments 6 (6)

Most common AEs (≥ 20% of pts), n (%)b N = 103Decreased appetite 29 (28)Fatigue 21 (20)Rash 21 (20)Pyrexia 21 (20)

Grade 3/4 TRAEs (≥ 5% of pts), n (%) N = 103Hypertension 10 (10)

Grade ≥ 3 atezolizumab AESIs requiring systemic corticosteroids, n (%)Pneumonitis 2 (2)Encephalitis autoimmune 1 (1)Drug-induced liver injury 1 (1)Colitis 1 (1)AST increased 1 (1)Gamma-Glutamyltransferase increased 1 (1)Diabetes mellitus 1 (1)Pancreatitis 1 (1)


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SLD change over time and duration of response per INV-assessed RECIST v1.1

+, censored value; DCR, disease control rate; NR, not reached; SLD, sum of longest diameter.Data cutoff: 26 July 2018.

DCR (CR+PR+SD), n/n (%) 56/73 (77)

≥ 16 wks 48/73 (66)

≥ 24 wks 34/73 (47)

Median DOR (range), mo NR(1.6+ to 22.0+)

≥ 6 mo, n/n (%) 12/23 (52)

≥ 12 mo, n/n (%) 6/23 (26)

Ongoing response, n/n (%) 19/23 (83)

Median follow-up, mo 7.2

Cha

nge

in S

LD fr

om B

asel

ine

(%)

Time (months)


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INV-assessed PFS per RECIST v1.1

+, censored.Data cutoff: 26 July 2018.

n = 73Median PFS (range), mo 14.9 (0.5 to 23.9+)

PFS events, n (%) 29 (40)

6-month PFS, % 65

Median follow-up, mo 7.2

§ The median OS has not been reached (range, 0.8 to 24.0+ mo)


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Best objective response and reduction in target lesion per IRF-assessed RECIST v1.1

+, censored value. a Four patients (6%) not evaluable or missing. b EHS/MVI baseline data missing from 1 patient.Data cutoff: 26 July 2018.

ORROverall, n/n (%)a 20/73 (27)

CR 4/73 (5)PR 16/73 (22)

SD 35/73 (48)DCR (CR+PR+SD) 55/73 (75)PD 14/73 (19)By aetiology, n/n (%)

HBV 9/36 (25)HCV 9/23 (39)Non-viral 2/14 (14)

By EHS/MVI, n/n (%)b

EHS and/or MVI 16/64 (25)MVI negative 11/32 (34)EHS negative 8/22 (36)Neither EHS nor MVI 4/8 (50)

Median DOR (range), mo NR (1.6+ to 22.0+)

≥ 6 mo, n/n (%) 9/20 (45)≥ 12 mo, n/n (%) 5/20 (25)

-100

-80

-60

-40

-20

0

20

40

60

80

100

• Median PFS was 7.5 mo (0.4 to 23.9+)

Max

imum

SLD

Red

uctio

n Fr

om B

asel

ine

(%)

CRPRSDPDNE


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Best objective response and reduction in target lesion per IRF-assessed HCC mRECIST

+, censored value.a Four patients (6%) not evaluable or missing. b EHS/MVI baseline data missing from 1 patient.Data cutoff: 26 July 2018.

-100

-80

-60

-40

-20

0

20

40

60

80

100

CRPRSDPDNE

HCC mRECIST takes into account tumour necrosis and includes contrast enhancement in arterial phase imaging

ORROverall, n/n (%)a 25/73 (34)

CR 8/73 (11)PR 17/73 (23)

SD 30/73 (41)DCR (CR+PR+SD) 55/73 (75)PD 14/73 (19)By aetiology, n/n (%)

HBV 13/36 (36)HCV 9/23 (39)Non-viral 3/14 (21)

By EHS/MVI, n/n (%)b

EHS and/or MVI 18/64 (28)MVI negative 15/32 (47)EHS negative 11/22 (50)Neither EHS nor MVI 7/8 (88)

Median DOR (range), mo NR (1.6+ to 22.0+)

≥ 6 mo, n/n (%) 10/25 (40)≥ 12 mo, n/n (%) 5/25 (20)

• Median PFS was 7.5 mo (0.4 to 23.9+)

Max

imum

SLD

Red

uctio

n Fr

om B

asel

ine

(%)


§ The combination of atezolizumab + bevacizumab was generally tolerable with a manageable safety profile § No new safety signals were identified beyond the established safety profile for each single agent

§ The combination of atezolizumab + bevacizumab showed promising activity§ The confirmed ORR was 32% per INV-assessed RECIST, 27% per IRF-assessed RECIST and

34% per IRF-assessed HCC mRECIST§ Responses were observed in all assessed patient subgroups, including aetiology, region, baseline AFP

and tumour burden (EHS and MVI) § Responses were durable, with 52% lasting for ≥ 6 months and 26% lasting for ≥ 12 months

per INV-assessed RECIST§ The confirmed CR was 1% per INV-assessed RECIST, 5% by IRF-assessed RECIST and

11% per IRF-assessed HCC mRECIST

§ Atezolizumab + bevacizumab may become a promising treatment option for patients with unresectable or advanced HCC§ The U.S. Food and Drug Administration has granted Breakthrough Therapy Designation

for atezolizumab in combination with bevacizumab as first-line treatment for patients with unresectable or advanced HCC

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Conclusions

RECIST, Response Evaluation Criteria in Solid Tumours v1.1.

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